Amorphous Ipatasertib Formulation for Stable Tablet Processing
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Solution Overview
Problem
Conventional pharmaceutical compositions and manufacturing processes for ipatasertib monohydrochloride face challenges due to its high brittleness, solubility, and hygroscopicity, leading to processing difficulties, lamination issues, and instability, which affect the quality and stability of the final product.
Innovation Solution
The use of intragranular materials with plastic deformation characteristics, such as microcrystalline cellulose, and moisture adsorbents, combined with a controlled fluid bed granulation and spray drying processes using a rotary wheel type atomizer, to produce amorphous ipatasertib monohydrochloride with improved particle properties and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If conventional mechanical compression is used for tabletting ipatasertib monohydrochloride, then the process is simple and direct, but the API exhibits highly brittle deformation characteristics leading to exhausted compressibility, elastic recovery, lamination problems, and crack formation
Solution Approach 1:
The patent changes the physical state of the API from crystalline to amorphous form, fundamentally altering its mechanical properties. This parameter change transforms the brittle deformation characteristics into plastic deformation behavior, enabling successful compression without lamination or cracking while maintaining process simplicity
Solution Approach 2:
The patent creates a composite system by combining amorphous ipatasertib monohydrochloride with specific excipients (microcrystalline cellulose, pregelatinized starch, colloidal silica) to form a granulated material. This composite approach enhances the mechanical properties of the API blend, providing both plastic deformation capability and moisture control
2Adaptability or versatility
If ipatasertib monohydrochloride is processed in conventional pharmaceutical compositions, then the API can be formulated, but its very high solubility and hygroscopicity cause auto-dissolution to viscous liquid at increased humidity, creating processing and stability problems
Solution Approach 1:
The patent introduces colloidal silica as an intermediary substance that absorbs excess moisture and prevents the API from auto-dissolving. This mediator material controls the humidity microenvironment around the hygroscopic API, maintaining its stability during processing and storage
Solution Approach 2:
The patent transforms the API from crystalline to amorphous form, which fundamentally changes its interaction with moisture. The amorphous form, when combined with moisture-absorbing excipients, exhibits improved hygroscopicity control compared to the crystalline form, preventing viscous liquid formation
3Productivity
If conventional drying processes are used for amorphous ipatasertib monohydrochloride, then the API can be processed, but long drying times at high temperatures and mandatory removal of less-preferred solvents are required, which can provoke partial crystallization
Solution Approach 1:
The patent employs spray drying with specific parameter optimization (atomization, drying temperature, airflow) to rapidly remove solvent at lower temperatures. This parameter control achieves complete drying within minutes while maintaining the amorphous form, preventing crystallization that occurs with conventional high-temperature prolonged drying
Solution Approach 2:
The patent replaces conventional thermal drying with spray drying technology, which uses atomization and rapid evaporation in a controlled aerosol state. This substitution enables much faster drying times (minutes vs. hours) at lower temperatures, preserving the amorphous structure
4Ease of manufacture
If conventional wet granulation processes are used for ipatasertib, then granules can be formed, but the high solubility and hygroscopicity of the API make the process difficult to control and require high amounts of moisture adsorbent (10-15% wt)
Solution Approach 1:
The patent changes the API form to amorphous and optimizes the excipient composition (specific ratios of microcrystalline cellulose, pregelatinized starch, and colloidal silica). This parameter change improves granulation processability and reduces moisture adsorbent requirements to 2-5% wt while maintaining granule quality
Solution Approach 2:
The patent creates a synergistic composite system where amorphous ipatasertib monohydrochloride is combined with moisture-absorbing excipients in optimized ratios. This composite approach provides both granulation functionality and moisture control with reduced adsorbent quantities compared to using crystalline API
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The solution results in stable, uniform, and high-quality amorphous ipatasertib monohydrochloride with enhanced flowability and bulk density, enabling efficient tablet production without additional treatments, and ensuring consistent product quality and stability.
Implementation Method 1
drying by spraying a feed solution in a spray dryer, thereby removing the solvent
Implementation Method 2
spraying a feed solution in a spray dryer
Data Source
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AI summary
The present invention relates to pharmaceutical compositions comprising Akt protein kinase inhibitors with therapeutic activity against diseases such as cancer as well as processes for their preparation and their use as medicament.